RENAL INJURY AND ADAPTATION TO HEME PROTEINS

Project: Research project

Project Details

Description

Heme oxygenase (HO) is the rate-limiting enzyme in the
degradation of heme. HO thus reduces cellular levels of heme, a
pro-oxidant, and ultimately procures bilirubin, an antioxidant. HO
exists as an oxidant and cytokine-inducible isoform, HO-1, and an
unresponsive constitutive isoform, HO-2, We demonstrate that
induction of HO-1 protects against oxidant injury imposed by heme
proteins and other toxins. These effects of HO-1 are contingent
upon synthesis of ferritin (the major intracellular iron-binding
protein), and possibly, induction of Heme Binding Protein 23 (an
inducible high affinity heme binding protein); this integrated
response limits the cytotoxicity of oxidants and cytokines incurred
as intracellular heme proteins are destabilized and heme is released.
We recently observed that HO-1 is upregulated in renal
inflammation and reduces susceptibility to subsequent insults. That
HO-1 is involved in inflammation and is a determinant if tissue
injury thus carries this enzyme beyond toxic nephropathies into
areas with timely and far-reaching biologic appeal. We propose 4
specific aims. The first specific aim is the development of
transgrenic models that overexpress HO-1 and ferritin, globally, as
well as regionally in the kidney; this approach complements
pharmacologic studies. We will test whether such animals are less
susceptible to toxic and inflammatory insults wherein we have
obtained evidence for a protective role for HO-1 and ferritin. The
second specific aim will examine induction of HO-1 and its allied
molecules as determinants of resistance to oxidant injury. Oxidant
injury represents a critical mechanism common to toxic and
inflammatory states, and we will analyze functional significance of
such induction in states of resistance to oxidative injury. The third
specific aim will examine the mechanisms and significance
underlying the induction of HO-1 we have observed in renal tubules
in acute glomerular inflammation, nephrotoxic serum nephritis; in
this TNFalpha-dependent model, HO-1 is induced in tubules and
protects against renal injury. The fourth specific aim will examine
the mechanisms and significance of induction of HO-1 in
macrophages in acute interstitial inflammation. Macrophages are
critical components in renal injury in general and in allograft
rejection in particular. In our characterized model of acute allograft
rejection we will pursue the mechanisms and significance of
induction of HO-1 in interstitial macrophages. Our proposed
application thus continues to pursue the functionality of HO-1, as it
utilized a new strategy, transgenic mice, and as it defines a new
area of involvement namely, renal inflammation.
StatusFinished
Effective start/end date8/1/936/30/19

ASJC

  • Medicine(all)